The objective of these experiments is to test the hypothesis that ET-1 plays an important role in regulating maternal systemic arterial blood pressure, systemic vascular resistance, uterine and renal hemodynamics, as well as renal permeability to proteins in nonpregnant and pregnant ewes. Aim 1 is to determine the dose of an ET-1 converting enzyme inhibitor required to block the conversion of big ET-1 to processed ET-1, and to determine if the endogenous production of ET-1 plays a role in modulating cardiovascular dynamics in pregnant and nonpregnant ewes. Aim 2 is to determine the systemic, uterine, and renal vascular responses to both local and intravenous infusion of ET-1. Aim 3 is to determine the mechanism by which the uterine artery becomes refractory to the vasoconstrictor actions of ET-1 during pregnancy. Aim 4 is to test the hypothesis that infusions of ET-1 results in hypertension, reduced uterine blood flow, hemoconcentration, and proteinuria in both pregnant and nonpregnant sheep.